title: The fate of PrP GPI-anchor signal peptide is modulated by P238S pathogenic mutation.
abstract: Glycosylphosphatidylinositol (GPI)-anchored proteins are localized to the plasma membrane via a C-terminally linked GPI anchor. The GPI anchor is added concomitantly to the cleavage of the carboxy-terminal GPI-anchor signal sequence, thereby causing the release of a C-terminal hydrophobic peptide, whose fate has not yet been investigated. Here we followed the fate of the GPI-attachment signal of the prion protein (PrP), a protein implicated in various types of transmissible neurodegenerative spongiform encephalopathies (TSE). The PrP GPI-anchor signal sequence shows a remarkable and unusual degree of conservation across the species and contains two point mutations (M232R/T and P238S) that are responsible for genetic forms of prion disorders. We show that the PrP GPI-anchor signal peptide (SP), but not the one from an unrelated GPI-anchored protein (folate receptor), undergoes degradation via the proteasome. Moreover, the P238S point mutation partially protects the PrP GPI-anchor SP from degradation. Our data provide the first attempt to address the fate of a GPI-anchor SP and identify a role for the P238S mutation, suggesting the possibility that the PrP GPI-anchor SP could play a role in neurodegenerative prion diseases.
authors.affiliation: Institut Pasteur, Unité de Trafic Membranaire et Pathogenèse, 25-28 rue du Docteur Roux, 75015, Paris, France.
authors.forename: Gianni
authors.initials: G
authors.lastname: Guizzunti
authors.forename: Chiara
authors.initials: C
authors.lastname: Zurzolo
mesh_terms: D000595:Amino Acid Sequence; D058973:Folate Receptors, GPI-Anchored / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D011328:Prions / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D021382:Protein Sorting Signals; D021381:Protein Transport; D059748:Proteolysis
chemical_list: D058973:Folate Receptors, GPI-Anchored; D011328:Prions; D021382:Protein Sorting Signals; D046988:Proteasome Endopeptidase Complex
keywords: GPI-anchor; PrP mutation; degradation; prion; proteasome; signal peptide